Multi-author Review

Cellular and Molecular Life Sciences

, Volume 67, Issue 10, pp 1567-1579

Tumor necrosis factor-mediated cell death: to break or to burst, that’s the question

  • Franky Van HerrewegheAffiliated withUnit For Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, VIBUnit for Molecular Signalling and Cell Death, Department of Biomedical Molecular Biology, Ghent University
  • , Nele FestjensAffiliated withUnit for Molecular Glycobiology, Department for Molecular Biomedical Research, VIB, Ghent UniversityLaboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University
  • , Wim DeclercqAffiliated withUnit For Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, VIBUnit for Molecular Signalling and Cell Death, Department of Biomedical Molecular Biology, Ghent University
  • , Peter VandenabeeleAffiliated withUnit For Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, VIBUnit for Molecular Signalling and Cell Death, Department of Biomedical Molecular Biology, Ghent University Email author 

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Abstract

In this review, we discuss the signal-transduction pathways of three major cellular responses induced by tumor necrosis factor (TNF): cell survival through NF-κB activation, apoptosis, and necrosis. Recruitment and activation of caspases plays a crucial role in the initiation and execution of TNF-induced apoptosis. However, experimental inhibition of caspases reveals an alternative cell death pathway, namely necrosis, also called necroptosis, suggesting that caspases actively suppress the latter outcome. TNF-induced necrotic cell death crucially depends on the kinase activity of receptor interacting protein serine-threonine kinase 1 (RIP1) and RIP3. It was recently demonstrated that ubiquitination of RIP1 determines whether it will function as a pro-survival or pro-cell death molecule. Deeper insight into the mechanisms that control the molecular switches between cell survival and cell death will help us to understand why TNF can exert so many different biological functions in the etiology and pathogenesis of human diseases.

Keywords

Tumor necrosis factor Apoptosis Necrosis Receptor interacting protein kinase 1